(Revised Abstract) DESCRIPTION: This Program was begun in 1999 to foster the establishment of a consortium of laboratories in the Boston- Cambridge area that shared a common interest in elucidating the molecular mechanisms of breast cancer development. The proposed Program will continue the monthly meetings and annual retreat of all researchers involved in the research sponsored by this Program. The participating groups have specific interests in various of the molecular and biological steps that cause normal human mammary epithelial cells (MECs) to develop progressively into carcinoma cells. David Livingston's research addresses the BRCA1 and allied proteins, defective forms of which are associated with the destabilization of the genome of MECs; recent research indicates that the BRCA1 gene may function in yet other ways to prevent the initiation of breast cancers. Joan Brugge's research is concentrated on characterizing the molecular mechanisms by which certain aberrantly functioning genes are able to perturb the morphogenesis of the acini in the mammary epithelium, thereby triggering some of the earliest histological abnormalities in the human breast. Mark Ewen's work is focused on understanding the molecular mechanism by which cyclin D1 -- a protein that is frequently over-expressed in human breast cancer cells -- is able to derail the normal proliferation and differentiation of human MECs. Peter Sicinski's research is directed toward understanding how mitogenic signals (normal or oncogenic) impinging on the surface of a MEC are able to communicate with the cell cycle apparatus in the nucleus of such a cell, in part by inducing expression of D-type cyclins. The work of Myles Brown addresses a similarly important attribute of many advanced breast carcinomas -- the actions of the estrogen receptor (ER) and the mechanisms through which collaborating transcriptional regulators (i.e., co-activators) are able to mediate the activating and suppressive functions of the ligandbound ER. Finally, Robert Weinberg's research is directed at three distinct areas of breast cancer development -- the reconstruction of normal breast tissue in mice, the possible role of prolactin in creating localized mammary hyperplasias, and the actions of a transcription factor in imparting the attributes of invasiveness and metastasis to already-tumorigenic MECs.